Inflammatory bowel disease (IBD) refers to a group of gastrointestinal (GI) disorders characterized by active inflammation of the colon and/or small intestine. The main forms of IBD are ulcerative colitis (UC) and Crohn's disease but also include collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behçet's syndrome and infective colitis. UC is restricted to the colon and the rectum while Crohn's disease can affect the entire GI tract, although most cases affect the lower part of the GI tract, starting in the terminal ileum and affecting the lower small intestine, colon and rectum. In addition, UC is restricted to the epithelial lining of the gut, while Crohn's disease can affect the whole bowel wall. Both UC and Crohn's disease can cause abdominal pain and diarrhea and may increase the risk of colorectal cancer. It is estimated that up to one million people in the US are affected by IBD, with male and female patients appearing to be equally affected.
About 10% of Americans older than 40 and about half of all people older than 60 have diverticulosis, which is a condition in which small pouches in the lining of the colon bulge outward through weak spots. These pouches, called diverticula, are most common in the lower portion of the colon. About 10 to 25% of people with diverticulosis develop diverticulitis, which is an inflammation or infection of the diverticula. Symptoms of diverticulitis include abdominal pain, fever, nausea and a change in bowel habits, and complications include bleeding, bowel perforations and blockages in the colon.
Colorectal cancer, also called colon cancer or large bowel cancer, refers to cancerous growths in the colon and rectum. Colorectal cancer is the fourth most common form of cancer in the US and is responsible for 655,000 deaths worldwide per year. Although colorectal cancer may be cured if found before it has metastasized, it often is not diagnosed until there has been significant metastasis, because it may cause no symptoms. Levels of uroguanylin and guanylin, which are the natural ligands of GC-C, are decreased or lost in colorectal cancer and activation of GC-C reverses the tumorigenic phenotype of colorectal cancer cells. Thus, it Hhas been suggested that colon cancer may be treated or prevented with oral supplementation with GC-C agonists (Li et al., Curr. Mol. Pharmacol. 2:285-92, 2009).
Given the prevalence of these disorders, a need exists to improve treatment options for IBD, diverticulitis, colorectal cancer as well as other disorders. Thus, there remains a need for new compounds and methods for treating these disorders.